Solid malignant tumors comprise the vast majority of all human cancers. The non-surgical treatment of patients with malignant solid tumors generally includes ionizing radiation and chemotherapy with cytotoxic chemotherapeutic agents, both of which are affected by the oxygenation status of the tumor. It is well established that oxygen is rapidly metabolized by tumor cells and has limited diffusion distance from vasculature in tissues. As tumors enlarge, their central area has deficient blood supply which results in hypoxic and necrotic tissues. As a whole, tumors comprise well-oxygenated, hypoxic and anoxic areas that respond differently to non-surgical therapeutic treatment. Radiation therapy does not effectively destroy hypoxic areas in tumors unless the radiation dose is increased several-fold above the dose necessary to destroy well-oxygenated areas of the same tumor. Chemotherapeutic agents differentiate between their toxicity toward subpopulations of well-oxygenated and hypoxic tumor sites. We propose that the modulation of the oxygenation and blood perfusion of tumors represents an opportunity to control the effectiveness of existing therapeutic chemotherapies with known safety and efficacy as cytotoxins. Studies have shown that the effectiveness of ionizing radiation and cytotoxic chemotherapeutic agents toward hypoxic solid tumors can be enhanced by modulating the blood flow and oxygenation of the tumors. Studies have shown that the effectiveness of certain cytotoxic chemotherapeutic agents toward hypoxic solid tumors can be enhanced by reducing the blood flow and oxygenation of the tumors.
Vasoactive drugs such as nitroprusside, hydralazine, arginine, and nitroglycerine can selectively reduce tumor blood flow and increase the percent of hypoxic areas in experimental tumors. Hydralazine, nicotinamide, epinephrine, norepinephrine, and nitroglycerin have also been reported to reduce the interstitial fluid pressure (IFP) in tumors. By promoting hypoxia in the tumor, the cytotoxicity of chemotherapeutic agents which are active in hypoxic conditions is enhanced. Unfortunately vasoactive drugs that are therapeutically effective in reducing tumor blood flow in patients are antihypertensive agents that would likely cause hypotension or other side-effects in normotensive patients when present in therapeutically effective plasma concentrations. There is a need for therapeutic compositions that mask the vasoactive properties of these antihypertensive agents in the systemic circulation, which target and deliver these “inactive” vasoactive agents to tumors where they can be “activated” and that provide therapy useful in the treatment of solid tumors with a hypoxic cytotoxic chemotherapeutic agent, radiotherapy or hyperthermia.
It is an object of the present invention to provide a method for treating a subject having a solid tumor comprising administering to the subject a tumor-targeted hydralazine conjugate in an amount effective in modulating tumor blood flow, oxygenation or interstitial fluid pressure.
It is an another object of the present invention to provide a method of enhancing the therapeutic efficacy of cytotoxic chemotherapeutic agents with co-administration of tumor-targeted hydralazine conjugates that selectively reduce blood flow and oxygenation of tumors in a subject having a solid tumor.
It is another object of the present invention to provide a method for treating a subject having a solid tumor comprising administering a chemotherapeutic agent in combination with a tumor-targeted hydralazine conjugate in an amount effective in decreasing tumor blood flow, oxygenation and interstitial fluid pressure.
It is another object of the present invention to provide a method for treating a subject having a solid tumor comprising administering a tumor-targeted hydralazine conjugate in an amount effective in modulating tumor blood flow, oxygenation and interstitial fluid pressure during radiological therapy.
It is another object of the present invention to provide a method for treating a subject having a solid tumor comprising administering a tumor-targeted hydralazine conjugate in an amount effective in decreasing tumor blood flow, oxygenation and interstitial fluid pressure during hyperthermia therapy.
It is another object of the present invention to provide compounds and a method for treating a subject having a tumor comprising administering a tumor-targeted hydralazine conjugate in an amount effective in modulating the inactivation of tumor suppression genes.